Clozapine Drug-Drug Interactions and Individualized Dosing in Bipolar Disorder: A Model-Informed Precision Dosing Approach.

OBJECTIVE

Clozapine is an effective treatment for bipolar disorder (BD), but its clinical use is complicated by drug-drug interactions (DDI), which may reduce efficacy or increase toxicity. This study aims to explore clozapine DDI and its individualized administration regimens for patients with BD based on model-informed precision dosing (MIPD) technology, and achieve clinical precision medication.

METHODS

Data are collected from 51 patients with BD treated with clozapine, including all concomitant medications used in clinical practice. The MIPD technique is used to explore the potential DDI, and the Monte Carlo simulation is adopted to recommend the optimal administration regimen.

RESULTS

It is ultimately found that zopiclone, zolpidem tartrate with clozapine have DDI. When patients with BD have no combined medication of zopiclone or zolpidem tartrate, the recommended doses of clozapine for patients at 40-45 kg, 45-60 kg, 60-78 kg, 78-106 kg, and 106-120 kg are 10 mg/kg/day, 9 mg/kg/day, 8 mg/kg/day, 7 mg/kg/day, and 6 mg/kg/day, respectively. When patients with BD are combined with zopiclone, the recommended doses of clozapine for patients at 40-60 kg and 60-120 kg are 4 mg/kg/day and 3 mg/kg/day, respectively. When patients with BD are combined with zolpidem tartrate, the recommended doses of clozapine for patients at 40-52 kg and 52-120 kg are 5 mg/kg/day and 4 mg/kg/day, respectively.

CONCLUSION

This study explores the DDI of clozapine in patients with BD based on MIPD, and recommends the individualized dosing regimen of clozapine in patients with BD according to concomitant medication. These findings provide weight- and drug-specific dosing recommendations that may improve the safety and efficacy of clozapine in BD patients.